A recent UCLA study on the actions of a cellular antioxidant regulator, Nrf2, found that it had some connection to the formation of atherosclerotic plaque, and that reducing Nrf2 decreased atherosclerosis. But should these study findings scare you away from eating Nrf2-promoting dietary antioxidants found in broccoli, blueberries, and dark chocolate, or from taking the so-called “anti-aging” supplement resveratrol?

It is known from several prior studies that one of the ways certain dietary antioxidants might promote health is through either boosting or normalizing the activity of the protein transcription factor, Nrf2, that helps to regulate the activity of other antioxidant and anti-inflammatory chemicals in the body. In fact, Nrf2 is thought of as a “master regulator” of the cell’s overall antioxidant response. Nrf2 activity is known to decline as we age, and is also thought to be stunted (in lung tissue) by toxins in cigarette smoke. The lungs of patients with COPD show markedly decreased levels of NRF2-dependent antioxidants, and a decrease in NRF2 protein.

Nrf2 activity, however, appears to be enhanced by certain dietary antioxidant compounds that are generally thought of as health-promoting. Epicatechin in dark chocolate appears to protect brain cells from stroke damage in part by turning on Nrf2 activity. Polyphenols in blueberries may be able to decrease liver fibrosis by increasing expression of Nrf2. Sulforaphane in cruciferous vegetables like broccoli and wasabi help normalize Nrf2 activity by reducing the action of KEAP1, a chemical known to inhibit Nrf2. Activation of sirtuin activity by resveratrol is also thought ultimately to enhance Nrf2 activity.

So with all of these prior findings of the likely benefits of optimizing Nrf2 levels and the activity of all its related proteins that protect and rejuvenate cells, what are we to make of this recent UCLA study?

The study was done by researchers hoping to find or at least to understand possible Nrf2 benefits for cardiovascular problems. Their findings, however, do not necessarily negate Nrf2 potential for optimizing health in humans. At this point they simply raise intriguing questions.

Considering the research design is important in trying to interpret this study. The researchers were studying mice, not humans or even human tissue. It was essentially a gene “knock-out” study – a useful but extreme and “unnatural” kind of study in which a gene that encodes for a particular RNA or protein is bred completely out of the entire organism. The lower level of atherosclerosis seen in the male (not female) study mice was found in the “unnatural” mice that completely lacked Nrf2. When some Nrf2 activity was added back in, the pattern of atherosclerosis returned to the “normal” pattern seen in regular mice.

Thus the study findings were actually that if all Nrf2 activity in male mice is totally eliminated, atherosclerosis in the aorta can be lowered by 53 percent compared to normal. The study does not say that modestly boosting Nrf2 activity above normal, or raising Nrf2 levels back to a normal range in old or sickly individuals, will accelerate atherosclerosis beyond its “normal” pace.

Also, no one is advocating blocking all Nrf2 activity as a way to reduce atherosclerotic plaque. And even if it did reduce plaque, the side-effects of such an extreme biological action would likely be devastating.

In conclusion, the study does not offer any evidence that aging baby-boomers concerned about their health should start limiting their dietary intake of berries, cruciferous vegetables, or dark chocolate or cocoa.

The Nrf2-knockout study, however, might be relevant for a certain group of high-risk patients with high cholesterol problems who continue to recklessly eat trans fats and fast foods, all the while taking high dose resveratrol thinking that the pill alone will save them. For such patients, it might be a good idea to have their doctor check both their lipid panel and their liver function tests (AST and ALT, for example) periodically, just to make sure their mega-dose supplement is not causing more harm than good, via as yet poorly understood Nrf2 pathways – John Zebrun, MD.